scholarly journals Anti-Inflammatory Activity of Dehydroandrographolide by TLR4/NF-κB Signaling Pathway Inhibition in Bile Duct-Ligated Mice

2018 ◽  
Vol 49 (3) ◽  
pp. 1124-1137 ◽  
Author(s):  
Zhiyong Weng ◽  
Yue Chi ◽  
Jing Xie ◽  
Xuefeng Liu ◽  
Jiehua Hu ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Kupffer Cells ◽  
Inflammatory Responses ◽  
Protective Effects ◽  
Bile Duct Proliferation ◽  
Duct Ligation ◽  
Anti Inflammatory ◽  
Cholestatic Liver Injury ◽  
Lps Binding

Background/Aims: Clinically, biliary obstruction is often accompanied by progressive inflammation. Dehydroandrographolide (DA) possesses anti-inflammatory properties. However, the anti-inflammatory activities of DA in cholestatic liver injury remain unclear. Methods: Mice were administered with DA by intraperitoneal injection after bile duct ligation (BDL) on day 1. Then mice were subjected to an ileocecal vein injection of lipopolysaccharide (LPS). Liver function markers, histology, pro-inflammatory cytokine levels, NF-κB activation and fibrosis formation were evaluated in BDL mice with LPS. LPS binding to primary Kupffer cells was examined by high-content cytometers. Results: DA was shown to greatly lower initially higher than normal levels of alanine aminotransferase (ALT) and total bilirubin (TBIL) in the serum and liver of BDL mice with LPS. DA exerted hepatic protective effects that were also confirmed by prolonged survival of BDL mice with LPS. Liver histopathology showed reduced inflammatory cellular infiltration, bile duct proliferation, and biliary necrosis with DA treatment. Furthermore, DA reduced the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in liver tissue and plasma and showed decreased NF-κB activation in BDL mice with LPS. DA could prevent LPS binding to primary Kupffer cells in the normal liver and BDL mice liver. DA also suppressed LPS-stimulated inflammatory responses by blocking the interaction between LPS and TLR4 in primary Kupffer cells and human LX-2 cells, thereby inhibiting NF-κB activation. Conclusion: DA inhibition of inflammation against liver damage following BDL with LPS may be a promising agent for the treatment of cholestatic liver injury.

Bid-mediated apoptosis does not contribute to cholestatic liver injury following bile duct ligation

2009 ◽  
Vol 47 (01) ◽  
Author(s):  
P Nalapareddy ◽  
S Schüngel ◽  
MP Manns ◽  
H Jaeschke ◽  
A Vogel
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Duct Ligation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

scholarly journals Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury

2018 ◽  
Vol 19 (9) ◽  
pp. 2509 ◽  
Author(s):  
Jing Zhang ◽  
Xin Guo ◽  
Taiji Hamada ◽  
Seiya Yokoyama ◽  
Yuka Nakamura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Critical Role ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Fibrotic Liver ◽  
Intrahepatic Bile Ducts ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

scholarly journals Cell-specific regulatory effects of CXCR2 on cholestatic liver injury

2019 ◽  
Vol 317 (6) ◽  
pp. G773-G783 ◽  
Author(s):  
Takanori Konishi ◽  
Rebecca M. Schuster ◽  
Holly S. Goetzman ◽  
Charles C. Caldwell ◽  
Alex B. Lentsch
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Liver Damage ◽  
Chemokine Receptor ◽  
Therapeutic Target ◽  
Bile Duct Ligation ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

scholarly journals C/EBP homologous protein-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury in mice

Hepatology ◽  
2018 ◽  
Vol 67 (4) ◽  
pp. 1441-1457 ◽  
Author(s):  
Runping Liu ◽  
Xiaojiaoyang Li ◽  
Zhiming Huang ◽  
Derrick Zhao ◽  
Bhagyalaxmi Sukka Ganesh ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Duct Ligation ◽  
Intestinal Epithelial ◽  
Homologous Protein ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Cholestatic liver injury model of bile duct ligation and the protection of Huang-Lian-Jie-Du decoction by NMR metabolomic profiling

RSC Advances ◽  
2015 ◽  
Vol 5 (81) ◽  
pp. 66200-66211 ◽  
Author(s):  
Dandan Wei ◽  
Shanting Liao ◽  
Junsong Wang ◽  
Minghua Yang ◽  
Lingyi Kong
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Treatment Effects ◽  
Bile Duct Ligation ◽  
Metabolomic Profiling ◽  
Injury Model ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Bile duct ligation (BDL) induced cholestasis in rats and the treatment effects of Huang-Lian-Jie-Du decoction (HLJDD) were investigated by NMR-based metabolomics approach: biphasic feature of BDL model and bilateral adjustment of HLJDD were found.

Deteriorating effect of fluvastatin on the cholestatic liver injury induced by bile duct ligation in rats

2011 ◽  
Vol 30 (1) ◽  
pp. 66-74 ◽  
Author(s):  
H. Lotková ◽  
P. Staňková ◽  
T. Roušar ◽  
O. Kučera ◽  
L. Kohoutek ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Duct Ligation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

scholarly journals Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

2018 ◽  
Vol 314 (3) ◽  
pp. G319-G333 ◽  
Author(s):  
Nadine Gehrke ◽  
Michael Nagel ◽  
Beate K. Straub ◽  
Marcus A. Wörns ◽  
Marcus Schuchmann ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Acids ◽  
Bile Duct Ligation ◽  
Ex Vivo ◽  
Mapk Signaling ◽  
Caspase 8 ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

scholarly journals Shenqi Fuzheng Injection impairs bile duct ligation-induced cholestatic liver injury in vivo

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Fei Cao ◽  
Peng Liu ◽  
Xianbin Zhang ◽  
Yanfen Hu ◽  
Xin Dong ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Protective Function ◽  
Ppar Γ ◽  
Duct Ligation ◽  
Shenqi Fuzheng Injection ◽  
Cox 2 ◽  
Factor Α ◽  
Cholestatic Liver Injury

Abstract Background and aim: The aim of the present study sought to determine the protective function of Shenqi Fuzheng Injection (SFI) in cholestatic liver injury. Methods: Cholestatic liver injury was induced in a 7-day bile duct-ligated (BDL) rat model. Rats were divided into three groups that were comprised of: (1) Sham; (2) BDL model; and (3) SFI treatment. The sham and BDL groups were treated with an appropriate volume of 0.9% sodium chloride as the vehicle, and the SFI group was administered SFI at a dose of 20 ml/kg/day, via tail vein injection. Results: SFI significantly (all at P<0.01) decreased the levels of serum aspartate aminotransferase and alanine aminotransferase as compared with the BDL group, which was associated with reduced severity of inflammatory cell infiltration and hepatic damage. Moreover, SFI significantly decreased the levels of hepatic interleukin-6 (P<0.01), tumor necrosis factor-α (P=0.041), and malondialdehyde (P=0.026), and significantly increased the levels of total superoxide dismutase (P<0.01), and the GSH/GSSG ratio (P=0.041) in the liver. Western blot analysis showed that SFI increased PPAR-γ expression; however, SFI treatment decreased cyclooxygenase-2 (COX-2) expression and the phosphorylation of NF-κBp65. Conclusions: These data demonstrated that SFI attenuated both inflammation and oxidative stress, and disrupted cholestatic liver injury. The involved mechanism was dependent, at least in part, on regulating PPAR-γ, COX-2, and NF-κBp65 expression.

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